Solution phase synthesis of beta-turn peptidomimetic cyclic salts

Abstract

The present disclosure relates to methods of preparing and crystallizing β-turn cyclic peptidomimetic salts of formula I: where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , X, Y and n are as defined in the specification. The present disclosure provides a more efficient route for preparing a crystalline form of a β-turn cyclic peptidomimetic compounds and salts thereof.

What is claimed is: 
     
       1. A method of preparing a salt of a β-turn peptidomimetic cyclic compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is hydrogen, C 1  to C 6  alkyl, aryl, or an amino acid side chain substituent of a natural or unnatural amino acid; 
 R 3  is hydrogen, C 1  to C 6  alkyl, aryl, or an amino acid side chain substituent of a natural or unnatural amino acid; 
 R 2  and R 4  are independently hydrogen or C 1  to C 6  alkyl, or R 1  and R 2  together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group, or R 3  and R 4  together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; 
 Y is selected from the group consisting of hydrogen, —NO 2 , — COOR 14 , —OC(R 14 ) 3 , —SO 3 R 14 , and —SO 2 R 14 ; 
 R 5 , R 6 , R 7 , R 8 , and R 9  are independently hydrogen or C 1  to C 6  alkyl; 
 R 10  is hydrogen, methyl, t-butyl, or a protecting group; and 
 each R 14  is hydrogen, alkyl or aryl; 
 X is selected from the group consisting of O, NR 9 , S, P, Se, C 1  to C 6  alkylene, SO, SO 2  and NH; and 
 n is 0, 1, 2, 3, 4 or 5; 
 
       
       the method comprising steps of: 
       (a) providing a protected linear peptidomimetic compound of formula (IV) 
       
         
           
           
               
               
           
         
         wherein:
 R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 10 , X, Y, and n have the meanings defined above; 
 R 11  and R 13  are independently hydrogen or a protecting group; 
 R 12  is a protecting group; 
 W 1  and W 3  are independently an amino acid side chain substituent of a natural or unnatural amino acid, less a hydrogen atom at the point of attachment to R 11  and R 13  respectively; and 
 
         Z is selected from the group consisting of F, Cl, Br and I; 
       
       (b) selectively deprotecting the compound of formula (IV) to form a partially protected linear peptidomimetic compound of formula (III) 
       
         
           
           
               
               
           
         
         wherein:
 R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 13 , W 1 , W 3 , X, Y, Z, and n have the meanings defined above; 
 
       
       (c) cyclizing the partially protected linear peptidomimetic compound of formula (III) to form a compound of formula (II) by an intramolecular aromatic nucleophilic substitution reaction 
       
         
           
           
               
               
           
         
         wherein:
 R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R 10 , R 11 , R 13 , W 1 , W 3 , X, Y, and n have the meanings defined above; and 
 
       
       (d) deprotecting all amino acid side chain protecting groups in the compound of formula (II) to obtain the salt of the β-turn peptidomimetic cyclic compound of formula (I). 
     
     
       2. The method of  claim 1  wherein the β-turn peptidomimetic cyclic compound of formula (I) has a macrocyclic ring of from 14 to 16 ring atoms. 
     
     
       3. The method of  claim 1  wherein R 1  and R 3  are independently a side chain substituent of two different amino acids. 
     
     
       4. The method of  claim 3  wherein R 1  and R 3  are independently a side chain substituent of lysine, glutamic acid, tyrosine, isoleucine, asparagine, arginine or threonine. 
     
     
       5. The method of  claim 1  wherein R 1  and R 3  are independently a side chain substitutent of glutamic acid, lysine, isoleucine or arginine. 
     
     
       6. The method of  claim 1  wherein R 11  and R 13  are independently selected from the group consisting of trifluoroacetyl, formyl, acetyl, t-butyloxycarbonyl (BOC), cyclohexyloxycarbonyl, fluorenyl-9-methoxy-carbonyl (Fmoc), benzyloxycarbonyl (Cbz), Cbz derivatives, triphenyl, methyl, benzyl, allyloxycarbonyl, tert-butyl, alkyl silane and allyl. 
     
     
       7. The method of  claim 1  wherein R 12  is trityl or tert-butyldimethylsilane (TBDMS). 
     
     
       8. The method of  claim 1  wherein W 1  and W 3  are independently a side chain substituent of lysine, glutamic acid, tyrosine, isoleucine, asparagine, arginine or threonine, less a hydrogen atom on the functional group. 
     
     
       9. The method of  claim 1  wherein X is O, S or NH. 
     
     
       10. The method of  claim 1  wherein Y is —NO 2 . 
     
     
       11. The method of  claim 1  wherein the cyclizing is performed in the presence of a base comprising t-BuOK, CsCO 3 , K 2 CO 3 , or mixtures thereof. 
     
     
       12. The method of  claim 1  wherein the cyclizing is performed in a polar aprotic solvent comprising acetonitrile, tetrahydrofuran, dioxanes, or mixtures thereof. 
     
     
       13. The method of  claim 1  wherein the cyclizing is performed in less than about 0.5% (v/v) of water and less than about 0.5% (v/v) of methanol. 
     
     
       14. The method of  claim 1  wherein the cyclizing is performed at a concentration lower than 0.05M of the partially protected linear peptidomimetic intermediate (III). 
     
     
       15. The method of  claim 1  wherein the cyclizing is performed at a temperature of from −20° C. to 15° C. 
     
     
       16. The method of  claim 1  wherein the deprotecting of step (d) is performed under a strong acidic condition using a HCl solution with a concentration of from 10% to 60% (v/v). 
     
     
       17. The method of  claim 1  wherein the salt is a pharmaceutically acceptable salt. 
     
     
       18. The method of  claim 16  wherein the salt is a HCl salt. 
     
     
       19. A method of preparing a β-turn peptidomimetic cyclic compound having the following structure: 
       
         
           
           
               
               
           
         
         the method comprising steps of: 
         (a) providing a protected linear peptidomimetic compound of formula (4a); 
       
       
         
           
           
               
               
           
         
         (b) selectively deprotecting the compound of formula (4a) to form a partially protected linear peptidomimetic compound of formula (3a); 
       
       
         
           
           
               
               
           
         
         (c) cyclizing the partially protected linear peptidomimetic compound of formula (3a) to form a compound of formula (2a) by an intramolecular aromatic nucleophilic substitution reaction; and 
       
       
         
           
           
               
               
           
         
         (d) deprotecting all amino acid side chain protecting groups in the compound of formula (2a) to obtain the HCl salt of D3. 
       
     
     
       20. The method of  claim 19  further comprises a step of deprotecting the compound of formula (2a) by suspending the compound in a mixture of a HCl solution and acetonitrile.